- Email: [email protected]
dysplastic” nevi with florid fibroplasia associated with pseudomelanomatous features
‘‘Clark/dysplastic’’ nevi with florid fibroplasia associated with pseudomelanomatous features Christine J. Ko, MD, Jean L. Bolognia, MD, and Earl J. Glusac, MD New Haven, Connecticut Background: Melanocytic nevi may exhibit histologic features in common with cutaneous melanoma, creating diagnostic difficulties. Objective: We sought to assess the clinical behavior of melanocytic nevi with pseudomelanomatous features in association with dermal fibrosis. Methods: Forty-two melanocytic nevi with pronounced fibrosis and associated pseudomelanomatous changes were collected and studied clinically and histologically. Results: The fibrosis was centrally located and laminated in appearance. It imparted a trizonal appearance: a junctional component with prominent single cells and/or irregular nests, underlying fibrosis, and a mature dermal component. No recurrence or metastases were evident over an average follow-up period of 2 years. Limitations: The follow-up period was short. Conclusions: The central location and laminated appearance of the fibrosis suggest that this may represent the extreme end of a spectrum of fibroplastic changes in ‘‘Clark/dysplastic’’ nevi. Adjacent features of ‘‘Clark/dysplastic’’ nevi and limitation of pseudomelanomatous features to the perifibrotic focus are important in accurately identifying these lesions. Although melanocytic nevi with exaggerated fibroplasia may show foci with melanoma-like features, they do not appear to exhibit aggressive clinical behavior. ( J Am Acad Dermatol 2011;64:346-51.) Key words: Atypical nevus; Clark nevus; dysplastic nevus; fibroplasia; melanoma; pseudomelanoma; sclerosing nevus.
INTRODUCTION In 1978 Clark and co-workers described the histopathologic features of melanocytic nevi from patients with multiple, clinically atypical nevi.1 These features included variable cytologic atypia, lentiginous growth pattern, lamellar/concentric fibroplasia, confluence of nests, and lateral extension of the junctional component plus dermal maturation in compound lesions.2 Nevi that display these histopathologic characteristics are termed ‘‘Clark’’ nevi by some authors3 and ‘‘atypical’’4 or ‘‘dysplastic’’5 nevi by others. Since the original
From the Departments of Dermatology and Pathology, Yale University School of Medicine. Funding sources: None. Conflicts of interest: None declared. Presented at the 46th Annual Meeting of the American Society of Dermatopathology, October 2009, Chicago, IL. Reprint requests: Christine J. Ko, 333 Cedar St, PO Box 208059, New Haven, CT 06520. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.046
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description, it has become clear that nevi with such features are more often sporadic than associated with a familial atypical mole/melanoma phenotype.5 While the majority of ‘‘Clark/dysplastic’’ nevi are easily recognized histopathologically, some are problematic. We describe a challenging subset with pronounced fibrosis and associated pseudomelanomatous features that has not been widely recognized,6 although other authors have described fibrotic nevi with varying degrees of similarity to the lesions herein reported. Terms employed included ‘‘nevus with regression-like fibrosis’’,7 ‘‘sclerosing nevus with pseudomelanomatous features’’, and ‘‘non-surgically traumatized nevus’’. The cause of the fibrosis and diversity and degree of pseudomelanomatous changes in such lesions has remained elusive.
MATERIAL AND METHODS Forty-two melanocytic nevi with fibrosis were gathered from the files of the Yale Dermatopathology Laboratory. These lesions were selected on the basis of the histopathologic presence
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of pronounced fibrosis plus the histologic features of atypia, bridging of elongated rete, lamellar fibroplasia, ‘‘Clark/dysplastic’’ nevus. Representative sections and lentiginous growth pattern. These changes surwere evaluated for cytologic atypia, bridging of rounded a central area of pronounced fibrosis. In rete, fibrosis, lateral extension of the junctional comspecimens containing all or almost all of the lesion ponent (in compound lesions), circumscription, (32/42; 76%), changes typical of ‘‘Clark/dysplastic’’ pagetoid spread, lentiginous pattern, and asymmenevus were present symmetrically around the fibrotic try. Where sufficient tissue was present, sections focus, and the lesions were well circumscribed. The were stained with HMB-45 fibrotic focus typically created (DAKO, Carpinteria, CA) (24 a vertically trizonal appearCAPSULE SUMMARY cases) and Ki-67 (DAKO) ance, characterized by (1) a (26 cases). Clinical informajunctional component with ‘‘Clark/dysplastic’’ nevi may have florid tion was obtained as follows: prominent single cells and/or fibroplasia and associated history of trauma to the irregular nests, (2) underlying pseudomelanomatous features lesion, personal/family hisfibrosis, and (3) a mature histopathologically. tory of melanoma, history of dermal component. The Key features of this type of nevus, which atypical nevi, presence of a exaggerated fibroplasia exis not associated with aggressive white/gray area, presence of tended to a mean depth of behavior, are ‘‘Clark/dysplastic’’ nevus atypical features clinically 0.5 mm. The fibroplasia symmetrically surrounding a zone of (asymmetry, border irreguformed a horizontally orifibrosis; pseudomelanomatous features larity, variegation of color, ented, plaque-like configurarestricted to an area of fibrosis; and size), history of change, and tion. In 5 lesions, the mature-appearing nevus below the area recurrence or lack of recurfibroplasia also extended in of fibrosis. rence of the lesion in question. an inverted triangular pattern, Request for review of prior the apex of which consisted material was made for patients of adventitial dermis surwith a history of melanoma or melanoma in situ. rounding a hair follicle. None of these 5 lesions exhibited inflammation of the follicle. RESULTS The fibrosis in all cases did not have the appearClinical features ance of a typical scar. No cases displayed thickened The mean age of the patients was 46 years (range, collagen arranged parallel to the epidermis. In all 18-91 years). There were 25 men and 16 women (one cases, the fibrosis was wavy and delicate and often male patient had 2 lesions). The most common site accentuated at the tips of elongated rete. was the trunk (33/42), with fewer lesions on the Overlying and within the central fibrotic focus, extremities (8/42). One lesion was from the neck. there was prominent confluence of junctional nests Biopsies were performed because of atypical clinical involving 6 or more retes in 24 of 42 cases (57%). Also features (ie, size [5 mm, irregular border, asymmeoverlying the fibrosis, a focally flattened rete ridge try, multiple colors), history (ie, new or changing), or pattern with a predominance of single melanocytes very dark coloration. Dermatoscopic findings were was present in 29 of 42 cases (69%) (Fig 1). not available for review. Cytologically atypical melanocytes involved the There was a history of trauma in only one of the sides of follicular infundibula in 13 of 42 cases 35 patients with adequate clinical data. Clinically, (31%) (Fig 2). Distorted dermal nests were present only 6 lesions had a documented white/gray area. in 34 of 42 cases (81%) (Fig 3). Some of the dermal Twenty-five of the nevi underwent re-excision. nests were of unusual size or shape (eg, elongated There was no recurrence of any of the lesions over nests of melanocytes). Often the melanocytes in a mean follow-up period of 2 years. these dermal nests were very small with visible Nine of 38 patients (24%) had a history of multiple melanin pigment. Ten cases (24%) showed upward clinically atypical nevi. Two patients had a family scatter of melanocytes within the epidermis. Scatter history of melanoma. By clinical history, 5 of 38 did not exceed a few small foci of 1 to 3 cells. In the 3 (13%) had a personal history of melanoma or mellesions with obvious solar elastosis, the solar elastoanoma in situ. We were able to obtain these specisis was present beneath the fibrosis. Cytologic atypia mens for review in 1 of these 5 patients. was judged to be severe in 17 cases (40%). Additional investigation was performed on those biopsy specimens with sufficient tissue for staining. Histopathologic features Twenty-one of 24 compound lesions (88%) showed See Figs 1-4. All lesions had architectural features of a nevoid labeling pattern of maturation, that is, ‘‘Clark/dysplastic’’ nevus, with variable cytologic d
d
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Fig 2. A, Irregularly nested melanocytes at dermoepidermal junction with follicular extension. There is a horizontally trizonal appearance with ‘‘Clark/dysplastic’’ nevus flanking the central fibrosis-like ‘‘bookends’’. B, Underlying the pseudomelanomatous junction (1), there are wavy fibrosis (2) and mature-appearing, nested melanocytes below the fibrosis (3). This imparts a vertically trizonal appearance to the lesion. Fig 1. A and B, Horizontally trizonal appearance with area of fibrosis flanked by ‘‘bookends’’ of ‘‘Clark/dysplastic’’ nevus. C, Architectural pattern is also vertically trizonal with an atypical junctional component and a flattened rete ridge pattern (1) overlying wavy dermal fibrosis (2), which overlies mature, nested dermal melanocytes (3).
junctional melanocytes and some superficial dermal melanocytes stained positively with HMB-45 (Fig 4). Of 26 compound lesions, all showed a low proliferation rate (\5% of dermal melanocytes) with Ki-67 staining.
DISCUSSION In this series of 42 melanocytic lesions, prominent central fibrosis was observed in conjunction with surrounding architectural features of standard ‘‘Clark/dysplastic’’ nevi. The wavy appearance of the fibrosis observed in these lesions suggests an exaggerated ‘‘Clark/dysplastic’’ type of fibroplasia, that is, laminated and concentric, as opposed to the denser collagen parallel to the epidermis admixed with fibroblasts seen in traumatic scars. In fact, these lesions appear to represent the extreme end of a spectrum of fibroplastic change within ‘‘Clark/dysplastic’’ nevi. One of the authors (E. J. G.) had the opportunity to show examples of these lesions to Wallace H. Clark, MD, shortly before his death in 1997. Dr Clark reported that he had seen this type of lesion many times, that they were usually found on the upper backs of older men, and that he had never seen one behave aggressively. Nevi with such prominent fibrosis have also been described as ‘‘sclerosing nevi with pseudomelanomatous features’’ and ‘‘nevi with regression-like fibrosis’’.6,7 Clinically, these lesions have a subtle white-tan (hypopigmented) to blue-gray central area that may be better appreciated on dermatoscopy.8
The restriction of pseudomelanomatous histopathologic features to areas of fibrosis is reminiscent of recurrent melanocytic nevi. Recurrent nevi were originally described as ‘‘pseudomelanoma’’ because of the striking histopathologic resemblance of some examples to melanoma.9-11 In recurrent nevi, the regenerated epidermis, with a poorly developed rete pattern and (sometimes) poor adherence to the dermis, may be a major factor in the pathogenesis of this architectural pattern.12 It seems likely that the presence of single melanocytes associated with a distorted or flattened rete ridge pattern in our cases is also due in large part to the underlying fibrosis and fibrosis-induced changes in melanocyte phenotype. However, we do not believe our lesions are recurrent nevi, as the vast majority of the lesions in our series lacked a history of trauma, and none, to the best of the clinicians’ knowledge, had previously undergone biopsy. Additionally, the fibrosis in our cases did not resemble scar-like fibrosis (as seen in recurrent nevi) but instead resembled lamellar fibroplasia. While in the process of preparing our manuscript, we noted a report of a series of 19 nevi with fibrosis and pseudomelanomatous features by Fabrizi et al,6 with several of their lesions showing histologic features that were similar to ours. In their series, there was an average follow-up of 6 years, with no evidence of recurrence or metastasis. Seven of 19 lesions were originally diagnosed histopathologically as melanoma, and they were all completely excised.6 The authors concluded that all these lesions represented melanocytic nevi, or at worst ‘‘dysplastic’’ nevi, with pseudomelanomatous features. Fabrizi and coworkers6 suggested that fibrosis in their cases might have been secondary to minor
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Fig 3. A, Irregularly nested melanocytes at junction, with follicular extension. There is a horizontally trizonal appearance with ‘‘Clark/dysplastic’’ nevus flanking the central fibrosis-like ‘‘bookends’’. B, There is a vertically trizonal appearance, irregularly nested melanocytes at the dermoepidermal junction with some melanocytes arranged as single units (1), underlying wavy fibrosis (2), and then somewhat elongated nests of small melanocytes with focal melanin pigment (3).
trauma, probably unnoticed by the patient. Interestingly, only 1 of 35 cases with obtainable clinical history in our series had a history of trauma. Although we cannot exclude the possibility of minor trauma or trauma unappreciated by patients, it seems unlikely that trauma is the cause of fibroplasia with a distinctly laminated pattern, as seen in ‘‘Clark/dysplastic’’ nevi. As nevi grow radially, it follows that the older, central portion of the lesion has a longer period of time to develop intrinsic fibrosis typical of ‘‘Clark/dysplastic’’ nevi. Additionally, in one study, 25% of 92 traumatized melanocytic nevi demonstrated dermal fibrosis that was presumably scar-like.13 Five of 38 (13%) of our patients with obtainable clinical data had a reported history of melanoma or melanoma in situ. One of the melanomas showed changes, in retrospect, that were similar to the patient’s nevus with prominent fibrosis, raising the possibility that the lesion may not have been malignant and that this histopathological pattern can be a ‘‘signature’’ pattern for a given patient.14 This case also emphasizes the diagnostic difficulty of distinguishing nevi with prominent fibrosis from cutaneous melanoma,7,15,16 as does the original diagnosis of melanoma in 7 of 19 of the lesions described by Fabrizi and coworkers.6 Unfortunately, the other 4 patients’ previously diagnosed lesions could not be obtained for review. It is conceivable that some or all of these lesions were ‘‘overdiagnosed’’ as melanoma. Therefore there is reason to speculate that the 13% incidence of melanoma and/or melanoma in situ in our patients may be inaccurately high. However, if 13% of our patients did indeed have melanoma, perhaps this pattern of ‘‘Clark/dysplastic’’ nevus with prominent fibrosis
Fig 4. A and B, The architectural pattern is vertically trizonal with an atypical junctional component (1) overlying wavy dermal fibrosis (2), which overlies mature, nested dermal melanocytes that are quite small (3). C, HMB-45 staining shows nevoid pattern of maturation.
represents, as a reflection of multiple atypical/dysplastic nevi, a risk factor for melanoma. The most important and most frequent differential diagnostic consideration is cutaneous melanoma.6,7 Our lesions showed features that can be seen in melanoma, including pagetoid scatter (24%), cytologic atypia (40%), downward displacement of solar elastosis (3/3 lesions with solar elastosis),17 prominent confluence of junctional nests (57%), a flattened rete ridge pattern (69%), extension into hair follicles (31%), and irregular dermal nests (81%). We deem these lesions to be pseudomelanomatous for several reasons as follows: (1) retention of overall symmetry; (2) in lesions with pagetoid spread of melanocytes, scatter was focal, comprising no more than several cells, and was restricted to the center of the lesion as in benign lesions10; (3) a low proliferation rate with Ki-67 staining18; and (4) a maturation gradient, both by light microscopy and with HMB-45 staining.19-21 Lastly (5), a major distinguishing characteristic of these lesions from melanoma is the restriction of the pseudomelanomatous changes to central areas of fibrosis. Certainly, all lesions with nevoid dermal nests and fibrosis are not nevi, and melanoma can show a nevoid appearance with foci of dermal fibrosis.7 Key histologic features in Table I summarize distinction of nevi with prominent fibrosis from melanoma. If any of the key features are absent, melanoma should be strongly considered. A limitation of our series is the short follow-up period and the unavailability of 4 of the lesions diagnosed as malignant melanocytic lesions in this series of patients. Further evaluation of these lesions over time would be optimal, with prospective
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Table I. Features of ‘‘Clark/dysplastic’’ nevi with prominent fibrosis Clinical features
Trunk, especially back Adults, average age 46 years
Key histopathologic features
Pseudomelanomatous features that may be present
Ancillary features
Centrally located fibrotic area
Confluent junctional nests Nevoid pattern of maturation (24/42; 57%) with HMB-45 staining Flattened rete ridge pattern with Low proliferation rate with Ki-67 Fibrosis wavy, reminiscent of staining single melanocytes (29/42; lamellar and concentric 69%) fibroplasia Male predominance Atypical junctional component Adnexal extension (13/42; 31%) limited to area above fibrosis Distorted dermal nests (34/42; 81%) and a maturing dermal Pagetoid scatter (10/42; 24%) component beneath the fibrosis (in compound lesions) Downward displacement of solar elastosis by the fibrosis (vertically trizonal ) (3/3 with solar elastosis; 100%) Typical features of Severe cytologic atypia ‘‘Clark/dysplastic’’ nevus as (17/42; 40%) ‘‘bookends’’ on either side of the central area (horizontally trizonal ) Absence of nodular growth pattern6
correlation with melanoma risk. A difficulty in studying the natural history of these lesions is that conservative excision of these lesions is often recommended and performed, particularly when cytologic atypia is pronounced and the margins are involved. Nonetheless, with increased recognition of these lesions clinically and histopathologically, future studies and perhaps molecular analysis may further elucidate the nature of these lesions. At present, the characteristic nevoid histopathologic features of these lesions and the lack of aggressive behavior support the supposition that they are not biologically worse than ‘‘Clark/dysplastic’’ nevi. REFERENCES 1. Clark WH, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanoma from heritable melanocytic lesions. Arch Dermatol 1978;114:732-8. 2. Piepkorn M, Barnhill RL. Chapter 5: Common acquired and atypical (dysplastic) melanocytic nevi. In: Barnhill RL, Piepkorn M, Busam K, editors. Pathology of melanocytic nevi and malignant melanoma. 2nd ed. New York: Springer; 2004. p. 51-110. 3. Ackerman AB, Milde P. Naming acquired melanocytic nevi: common and dysplastic, normal and atypical, or Unna, Miescher, Spitz, and Clark? Am J Dermatopathol 1992;14: 447-53. 4. Shapiro M, Chren MM, Levy RM, Elder DE, LeBoit PE, Mihm MC Jr, et al. Variability in nomenclature used for nevi with architectural disorder and cytologic atypia (microscopically dysplastic nevi) by dermatologists and dermatopathologists. J Cutan Pathol 2004;31:523-30. 5. Elder DE. The dysplastic nevus. Pathology 1985;17:291-7. 6. Fabrizi G, Pennacchia I, Pagliarello C, Massi G. Sclerosing nevus with pseudomelanomatous features. J Cutan Pathol 2008;35: 995-1002.
7. Ferrara G, Amantea A, Argenziano G, Broganelli P, Cesinaro AM, Donati P, et al. Sclerosing nevus with pseudomelanomatous features and regressing melanoma with nevoid features. J Cutan Pathol 2009;36:913-5. 8. Kornberg R, Ackerman AB. Pseudomelanoma. Recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975;111:1588-90. 9. Ferrara G, Giorgio CM, Zalaudek I, Broganelli P, Pellacani G, Tomasini C, et al. Sclerosing nevus with pseudomelanomatous features (nevus with regression-like fibrosis): clinical and dermoscopic features of a recently characterized histopathologic entity. Dermatology 2009;219:202-8. Epub 2009 Jul 8. 10. Haupt HM, Stern JB. Pagetoid melanocytosis. Histologic features in benign and malignant lesions. Am J Surg Pathol 1995; 19:792-7. 11. Park HK, Leonard DD, Arrington JH, Lund HZ. Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 1987;17:285-92. 12. Clark WH, Tucker MA, Goldstein AM. Parenchymal-stromal interactions in neoplasia: theoretical considerations and observations in melanocytic neoplasia. Acta Oncol 1995;34: 749-57. 13. Selim MA, Vollmer RT, Herman CM, Pham TTN, Turner JW. Melanocytic nevi with nonsurgical trauma: a histopathologic study. Am J Dermatopathol 2007;29:134-6. 14. Suh KY, Bolognia JL. Signature nevi. J Am Acad Dermatol 2009; 60:508-14. 15. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera F, Brunetti B, et al. Dermoscopic and histopathologic diagnosis of equivocal melanocytic skin lesions. An interdisciplinary study on 107 cases. Cancer 2002;95:1094-100. 16. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Corona R, Sera F, et al. Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study. Br J Dermatol 2004;150:64-71. 17. Horenstein MG, Norton CL, Evans TN. Displacement of dermal solar elastosis in malignant melanoma. J Cutan Pathol 2007;34: 376-80.
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18. Smolle J, Soyer HP, Kerl H. Proliferative activity of cutaneous melanocytic tumors defined by Ki-67 monoclonal antibody. A quantitative immunohistochemical study. Am J Dermatopathol 1989;11:301-7. 19. Gown AM, Bogel AM, Hoak D, Gough F, McNutt MA. Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes. Am J Pathol 1986;123: 195-203.
20. Colombari R, Bonetti F, Zamboni G, Scarpa A, Marino F, Tomezzoli A, et al. Distribution of melanoma specific antibody (HMB-45) in benign and malignant melanocytic tumors. An immunohistochemical study on paraffin sections. Virchows Archiv A Pathol Anat Histopathol 1988;413:17-24. 21. Hoang MP, Prieto VG, Burchette JL, Shea CR. Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation. J Cutan Pathol 2001;28:400-6.
INTRODUCTION In 1978 Clark and co-workers described the histopathologic features of melanocytic nevi from patients with multiple, clinically atypical nevi.1 These features included variable cytologic atypia, lentiginous growth pattern, lamellar/concentric fibroplasia, confluence of nests, and lateral extension of the junctional component plus dermal maturation in compound lesions.2 Nevi that display these histopathologic characteristics are termed ‘‘Clark’’ nevi by some authors3 and ‘‘atypical’’4 or ‘‘dysplastic’’5 nevi by others. Since the original
From the Departments of Dermatology and Pathology, Yale University School of Medicine. Funding sources: None. Conflicts of interest: None declared. Presented at the 46th Annual Meeting of the American Society of Dermatopathology, October 2009, Chicago, IL. Reprint requests: Christine J. Ko, 333 Cedar St, PO Box 208059, New Haven, CT 06520. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.046
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description, it has become clear that nevi with such features are more often sporadic than associated with a familial atypical mole/melanoma phenotype.5 While the majority of ‘‘Clark/dysplastic’’ nevi are easily recognized histopathologically, some are problematic. We describe a challenging subset with pronounced fibrosis and associated pseudomelanomatous features that has not been widely recognized,6 although other authors have described fibrotic nevi with varying degrees of similarity to the lesions herein reported. Terms employed included ‘‘nevus with regression-like fibrosis’’,7 ‘‘sclerosing nevus with pseudomelanomatous features’’, and ‘‘non-surgically traumatized nevus’’. The cause of the fibrosis and diversity and degree of pseudomelanomatous changes in such lesions has remained elusive.
MATERIAL AND METHODS Forty-two melanocytic nevi with fibrosis were gathered from the files of the Yale Dermatopathology Laboratory. These lesions were selected on the basis of the histopathologic presence
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of pronounced fibrosis plus the histologic features of atypia, bridging of elongated rete, lamellar fibroplasia, ‘‘Clark/dysplastic’’ nevus. Representative sections and lentiginous growth pattern. These changes surwere evaluated for cytologic atypia, bridging of rounded a central area of pronounced fibrosis. In rete, fibrosis, lateral extension of the junctional comspecimens containing all or almost all of the lesion ponent (in compound lesions), circumscription, (32/42; 76%), changes typical of ‘‘Clark/dysplastic’’ pagetoid spread, lentiginous pattern, and asymmenevus were present symmetrically around the fibrotic try. Where sufficient tissue was present, sections focus, and the lesions were well circumscribed. The were stained with HMB-45 fibrotic focus typically created (DAKO, Carpinteria, CA) (24 a vertically trizonal appearCAPSULE SUMMARY cases) and Ki-67 (DAKO) ance, characterized by (1) a (26 cases). Clinical informajunctional component with ‘‘Clark/dysplastic’’ nevi may have florid tion was obtained as follows: prominent single cells and/or fibroplasia and associated history of trauma to the irregular nests, (2) underlying pseudomelanomatous features lesion, personal/family hisfibrosis, and (3) a mature histopathologically. tory of melanoma, history of dermal component. The Key features of this type of nevus, which atypical nevi, presence of a exaggerated fibroplasia exis not associated with aggressive white/gray area, presence of tended to a mean depth of behavior, are ‘‘Clark/dysplastic’’ nevus atypical features clinically 0.5 mm. The fibroplasia symmetrically surrounding a zone of (asymmetry, border irreguformed a horizontally orifibrosis; pseudomelanomatous features larity, variegation of color, ented, plaque-like configurarestricted to an area of fibrosis; and size), history of change, and tion. In 5 lesions, the mature-appearing nevus below the area recurrence or lack of recurfibroplasia also extended in of fibrosis. rence of the lesion in question. an inverted triangular pattern, Request for review of prior the apex of which consisted material was made for patients of adventitial dermis surwith a history of melanoma or melanoma in situ. rounding a hair follicle. None of these 5 lesions exhibited inflammation of the follicle. RESULTS The fibrosis in all cases did not have the appearClinical features ance of a typical scar. No cases displayed thickened The mean age of the patients was 46 years (range, collagen arranged parallel to the epidermis. In all 18-91 years). There were 25 men and 16 women (one cases, the fibrosis was wavy and delicate and often male patient had 2 lesions). The most common site accentuated at the tips of elongated rete. was the trunk (33/42), with fewer lesions on the Overlying and within the central fibrotic focus, extremities (8/42). One lesion was from the neck. there was prominent confluence of junctional nests Biopsies were performed because of atypical clinical involving 6 or more retes in 24 of 42 cases (57%). Also features (ie, size [5 mm, irregular border, asymmeoverlying the fibrosis, a focally flattened rete ridge try, multiple colors), history (ie, new or changing), or pattern with a predominance of single melanocytes very dark coloration. Dermatoscopic findings were was present in 29 of 42 cases (69%) (Fig 1). not available for review. Cytologically atypical melanocytes involved the There was a history of trauma in only one of the sides of follicular infundibula in 13 of 42 cases 35 patients with adequate clinical data. Clinically, (31%) (Fig 2). Distorted dermal nests were present only 6 lesions had a documented white/gray area. in 34 of 42 cases (81%) (Fig 3). Some of the dermal Twenty-five of the nevi underwent re-excision. nests were of unusual size or shape (eg, elongated There was no recurrence of any of the lesions over nests of melanocytes). Often the melanocytes in a mean follow-up period of 2 years. these dermal nests were very small with visible Nine of 38 patients (24%) had a history of multiple melanin pigment. Ten cases (24%) showed upward clinically atypical nevi. Two patients had a family scatter of melanocytes within the epidermis. Scatter history of melanoma. By clinical history, 5 of 38 did not exceed a few small foci of 1 to 3 cells. In the 3 (13%) had a personal history of melanoma or mellesions with obvious solar elastosis, the solar elastoanoma in situ. We were able to obtain these specisis was present beneath the fibrosis. Cytologic atypia mens for review in 1 of these 5 patients. was judged to be severe in 17 cases (40%). Additional investigation was performed on those biopsy specimens with sufficient tissue for staining. Histopathologic features Twenty-one of 24 compound lesions (88%) showed See Figs 1-4. All lesions had architectural features of a nevoid labeling pattern of maturation, that is, ‘‘Clark/dysplastic’’ nevus, with variable cytologic d
d
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Fig 2. A, Irregularly nested melanocytes at dermoepidermal junction with follicular extension. There is a horizontally trizonal appearance with ‘‘Clark/dysplastic’’ nevus flanking the central fibrosis-like ‘‘bookends’’. B, Underlying the pseudomelanomatous junction (1), there are wavy fibrosis (2) and mature-appearing, nested melanocytes below the fibrosis (3). This imparts a vertically trizonal appearance to the lesion. Fig 1. A and B, Horizontally trizonal appearance with area of fibrosis flanked by ‘‘bookends’’ of ‘‘Clark/dysplastic’’ nevus. C, Architectural pattern is also vertically trizonal with an atypical junctional component and a flattened rete ridge pattern (1) overlying wavy dermal fibrosis (2), which overlies mature, nested dermal melanocytes (3).
junctional melanocytes and some superficial dermal melanocytes stained positively with HMB-45 (Fig 4). Of 26 compound lesions, all showed a low proliferation rate (\5% of dermal melanocytes) with Ki-67 staining.
DISCUSSION In this series of 42 melanocytic lesions, prominent central fibrosis was observed in conjunction with surrounding architectural features of standard ‘‘Clark/dysplastic’’ nevi. The wavy appearance of the fibrosis observed in these lesions suggests an exaggerated ‘‘Clark/dysplastic’’ type of fibroplasia, that is, laminated and concentric, as opposed to the denser collagen parallel to the epidermis admixed with fibroblasts seen in traumatic scars. In fact, these lesions appear to represent the extreme end of a spectrum of fibroplastic change within ‘‘Clark/dysplastic’’ nevi. One of the authors (E. J. G.) had the opportunity to show examples of these lesions to Wallace H. Clark, MD, shortly before his death in 1997. Dr Clark reported that he had seen this type of lesion many times, that they were usually found on the upper backs of older men, and that he had never seen one behave aggressively. Nevi with such prominent fibrosis have also been described as ‘‘sclerosing nevi with pseudomelanomatous features’’ and ‘‘nevi with regression-like fibrosis’’.6,7 Clinically, these lesions have a subtle white-tan (hypopigmented) to blue-gray central area that may be better appreciated on dermatoscopy.8
The restriction of pseudomelanomatous histopathologic features to areas of fibrosis is reminiscent of recurrent melanocytic nevi. Recurrent nevi were originally described as ‘‘pseudomelanoma’’ because of the striking histopathologic resemblance of some examples to melanoma.9-11 In recurrent nevi, the regenerated epidermis, with a poorly developed rete pattern and (sometimes) poor adherence to the dermis, may be a major factor in the pathogenesis of this architectural pattern.12 It seems likely that the presence of single melanocytes associated with a distorted or flattened rete ridge pattern in our cases is also due in large part to the underlying fibrosis and fibrosis-induced changes in melanocyte phenotype. However, we do not believe our lesions are recurrent nevi, as the vast majority of the lesions in our series lacked a history of trauma, and none, to the best of the clinicians’ knowledge, had previously undergone biopsy. Additionally, the fibrosis in our cases did not resemble scar-like fibrosis (as seen in recurrent nevi) but instead resembled lamellar fibroplasia. While in the process of preparing our manuscript, we noted a report of a series of 19 nevi with fibrosis and pseudomelanomatous features by Fabrizi et al,6 with several of their lesions showing histologic features that were similar to ours. In their series, there was an average follow-up of 6 years, with no evidence of recurrence or metastasis. Seven of 19 lesions were originally diagnosed histopathologically as melanoma, and they were all completely excised.6 The authors concluded that all these lesions represented melanocytic nevi, or at worst ‘‘dysplastic’’ nevi, with pseudomelanomatous features. Fabrizi and coworkers6 suggested that fibrosis in their cases might have been secondary to minor
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Fig 3. A, Irregularly nested melanocytes at junction, with follicular extension. There is a horizontally trizonal appearance with ‘‘Clark/dysplastic’’ nevus flanking the central fibrosis-like ‘‘bookends’’. B, There is a vertically trizonal appearance, irregularly nested melanocytes at the dermoepidermal junction with some melanocytes arranged as single units (1), underlying wavy fibrosis (2), and then somewhat elongated nests of small melanocytes with focal melanin pigment (3).
trauma, probably unnoticed by the patient. Interestingly, only 1 of 35 cases with obtainable clinical history in our series had a history of trauma. Although we cannot exclude the possibility of minor trauma or trauma unappreciated by patients, it seems unlikely that trauma is the cause of fibroplasia with a distinctly laminated pattern, as seen in ‘‘Clark/dysplastic’’ nevi. As nevi grow radially, it follows that the older, central portion of the lesion has a longer period of time to develop intrinsic fibrosis typical of ‘‘Clark/dysplastic’’ nevi. Additionally, in one study, 25% of 92 traumatized melanocytic nevi demonstrated dermal fibrosis that was presumably scar-like.13 Five of 38 (13%) of our patients with obtainable clinical data had a reported history of melanoma or melanoma in situ. One of the melanomas showed changes, in retrospect, that were similar to the patient’s nevus with prominent fibrosis, raising the possibility that the lesion may not have been malignant and that this histopathological pattern can be a ‘‘signature’’ pattern for a given patient.14 This case also emphasizes the diagnostic difficulty of distinguishing nevi with prominent fibrosis from cutaneous melanoma,7,15,16 as does the original diagnosis of melanoma in 7 of 19 of the lesions described by Fabrizi and coworkers.6 Unfortunately, the other 4 patients’ previously diagnosed lesions could not be obtained for review. It is conceivable that some or all of these lesions were ‘‘overdiagnosed’’ as melanoma. Therefore there is reason to speculate that the 13% incidence of melanoma and/or melanoma in situ in our patients may be inaccurately high. However, if 13% of our patients did indeed have melanoma, perhaps this pattern of ‘‘Clark/dysplastic’’ nevus with prominent fibrosis
Fig 4. A and B, The architectural pattern is vertically trizonal with an atypical junctional component (1) overlying wavy dermal fibrosis (2), which overlies mature, nested dermal melanocytes that are quite small (3). C, HMB-45 staining shows nevoid pattern of maturation.
represents, as a reflection of multiple atypical/dysplastic nevi, a risk factor for melanoma. The most important and most frequent differential diagnostic consideration is cutaneous melanoma.6,7 Our lesions showed features that can be seen in melanoma, including pagetoid scatter (24%), cytologic atypia (40%), downward displacement of solar elastosis (3/3 lesions with solar elastosis),17 prominent confluence of junctional nests (57%), a flattened rete ridge pattern (69%), extension into hair follicles (31%), and irregular dermal nests (81%). We deem these lesions to be pseudomelanomatous for several reasons as follows: (1) retention of overall symmetry; (2) in lesions with pagetoid spread of melanocytes, scatter was focal, comprising no more than several cells, and was restricted to the center of the lesion as in benign lesions10; (3) a low proliferation rate with Ki-67 staining18; and (4) a maturation gradient, both by light microscopy and with HMB-45 staining.19-21 Lastly (5), a major distinguishing characteristic of these lesions from melanoma is the restriction of the pseudomelanomatous changes to central areas of fibrosis. Certainly, all lesions with nevoid dermal nests and fibrosis are not nevi, and melanoma can show a nevoid appearance with foci of dermal fibrosis.7 Key histologic features in Table I summarize distinction of nevi with prominent fibrosis from melanoma. If any of the key features are absent, melanoma should be strongly considered. A limitation of our series is the short follow-up period and the unavailability of 4 of the lesions diagnosed as malignant melanocytic lesions in this series of patients. Further evaluation of these lesions over time would be optimal, with prospective
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Table I. Features of ‘‘Clark/dysplastic’’ nevi with prominent fibrosis Clinical features
Trunk, especially back Adults, average age 46 years
Key histopathologic features
Pseudomelanomatous features that may be present
Ancillary features
Centrally located fibrotic area
Confluent junctional nests Nevoid pattern of maturation (24/42; 57%) with HMB-45 staining Flattened rete ridge pattern with Low proliferation rate with Ki-67 Fibrosis wavy, reminiscent of staining single melanocytes (29/42; lamellar and concentric 69%) fibroplasia Male predominance Atypical junctional component Adnexal extension (13/42; 31%) limited to area above fibrosis Distorted dermal nests (34/42; 81%) and a maturing dermal Pagetoid scatter (10/42; 24%) component beneath the fibrosis (in compound lesions) Downward displacement of solar elastosis by the fibrosis (vertically trizonal ) (3/3 with solar elastosis; 100%) Typical features of Severe cytologic atypia ‘‘Clark/dysplastic’’ nevus as (17/42; 40%) ‘‘bookends’’ on either side of the central area (horizontally trizonal ) Absence of nodular growth pattern6
correlation with melanoma risk. A difficulty in studying the natural history of these lesions is that conservative excision of these lesions is often recommended and performed, particularly when cytologic atypia is pronounced and the margins are involved. Nonetheless, with increased recognition of these lesions clinically and histopathologically, future studies and perhaps molecular analysis may further elucidate the nature of these lesions. At present, the characteristic nevoid histopathologic features of these lesions and the lack of aggressive behavior support the supposition that they are not biologically worse than ‘‘Clark/dysplastic’’ nevi. REFERENCES 1. Clark WH, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanoma from heritable melanocytic lesions. Arch Dermatol 1978;114:732-8. 2. Piepkorn M, Barnhill RL. Chapter 5: Common acquired and atypical (dysplastic) melanocytic nevi. In: Barnhill RL, Piepkorn M, Busam K, editors. Pathology of melanocytic nevi and malignant melanoma. 2nd ed. New York: Springer; 2004. p. 51-110. 3. Ackerman AB, Milde P. Naming acquired melanocytic nevi: common and dysplastic, normal and atypical, or Unna, Miescher, Spitz, and Clark? Am J Dermatopathol 1992;14: 447-53. 4. Shapiro M, Chren MM, Levy RM, Elder DE, LeBoit PE, Mihm MC Jr, et al. Variability in nomenclature used for nevi with architectural disorder and cytologic atypia (microscopically dysplastic nevi) by dermatologists and dermatopathologists. J Cutan Pathol 2004;31:523-30. 5. Elder DE. The dysplastic nevus. Pathology 1985;17:291-7. 6. Fabrizi G, Pennacchia I, Pagliarello C, Massi G. Sclerosing nevus with pseudomelanomatous features. J Cutan Pathol 2008;35: 995-1002.
7. Ferrara G, Amantea A, Argenziano G, Broganelli P, Cesinaro AM, Donati P, et al. Sclerosing nevus with pseudomelanomatous features and regressing melanoma with nevoid features. J Cutan Pathol 2009;36:913-5. 8. Kornberg R, Ackerman AB. Pseudomelanoma. Recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975;111:1588-90. 9. Ferrara G, Giorgio CM, Zalaudek I, Broganelli P, Pellacani G, Tomasini C, et al. Sclerosing nevus with pseudomelanomatous features (nevus with regression-like fibrosis): clinical and dermoscopic features of a recently characterized histopathologic entity. Dermatology 2009;219:202-8. Epub 2009 Jul 8. 10. Haupt HM, Stern JB. Pagetoid melanocytosis. Histologic features in benign and malignant lesions. Am J Surg Pathol 1995; 19:792-7. 11. Park HK, Leonard DD, Arrington JH, Lund HZ. Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 1987;17:285-92. 12. Clark WH, Tucker MA, Goldstein AM. Parenchymal-stromal interactions in neoplasia: theoretical considerations and observations in melanocytic neoplasia. Acta Oncol 1995;34: 749-57. 13. Selim MA, Vollmer RT, Herman CM, Pham TTN, Turner JW. Melanocytic nevi with nonsurgical trauma: a histopathologic study. Am J Dermatopathol 2007;29:134-6. 14. Suh KY, Bolognia JL. Signature nevi. J Am Acad Dermatol 2009; 60:508-14. 15. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera F, Brunetti B, et al. Dermoscopic and histopathologic diagnosis of equivocal melanocytic skin lesions. An interdisciplinary study on 107 cases. Cancer 2002;95:1094-100. 16. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Corona R, Sera F, et al. Clinically equivocal melanocytic skin lesions with features of regression: a dermoscopic-pathological study. Br J Dermatol 2004;150:64-71. 17. Horenstein MG, Norton CL, Evans TN. Displacement of dermal solar elastosis in malignant melanoma. J Cutan Pathol 2007;34: 376-80.
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18. Smolle J, Soyer HP, Kerl H. Proliferative activity of cutaneous melanocytic tumors defined by Ki-67 monoclonal antibody. A quantitative immunohistochemical study. Am J Dermatopathol 1989;11:301-7. 19. Gown AM, Bogel AM, Hoak D, Gough F, McNutt MA. Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes. Am J Pathol 1986;123: 195-203.
20. Colombari R, Bonetti F, Zamboni G, Scarpa A, Marino F, Tomezzoli A, et al. Distribution of melanoma specific antibody (HMB-45) in benign and malignant melanocytic tumors. An immunohistochemical study on paraffin sections. Virchows Archiv A Pathol Anat Histopathol 1988;413:17-24. 21. Hoang MP, Prieto VG, Burchette JL, Shea CR. Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation. J Cutan Pathol 2001;28:400-6.